This protocol is designed to study the natural history and epidemiology of hepatitis C virus (HCV) infection in an asymptomatic blood donor population, to assess the potential for sexual transmission or other percutaneous transmission of HCV and to assess the clinical impact of acute or chronic hepatitis B virus (HBV) infection superimposed on HCV infection. To date, the primary study has enrolled 760 patients. Of those 760 enrolled, 738 subjects have been analyzed, including 469 recombinant immunoblot assay (RIBA) positives, 52 RIBA indeterminates, and 217 RIBA-negative controls. The 15 year follow-up of the cohort was published in 2012(JID 2012:206:654). Interesting epidemiologic findings include the high proportion (41 percent) of RIBA+ donors who admitted to prior (remote) intravenous drug use and the strong independent association between cocaine snorting and HCV positivity. Shared paraphernalia for snorting accompanied by epistaxis, may serve as a covert vehicle for parenteral viral transmission. Among anti-HCV+/RIBA-positive donors, 82 percent were persistently viremic, but 18 percent appeared to have spontaneously recovered from prior HCV infection. A liver biopsy has been obtained from 185(47%) patients who were chronically infected; 51% had mild chronic hepatitis and 44% had moderate chronic hepatitis over a mean duration of infection of 20 years; only 5% had severe inflammation. No fibrosis was observed in 33% of biopsied patients and 52% had only mild fibrosis; 15 had more severe fibrosis including 12% with bridging fibrosis and 2% with cirrhosis. Overall, HCV infection in this cohort was generally asymptomatic and over the course of 25 years progressed to severe liver disease in approximately 15%. Despite an association of HCV with sexually promiscuous practices, we found no evidence for sexual transmission to the specific partners of 165 HCV-infected individuals. The study continues to follow the natural history of HCV infection and is now focusing on histologic progression as assessed in liver biopsies and fibroscans. New emphasis is being placed on studies of cell-mediated immune responses to HCV, neutralizing antibody responses, predictors of fibrosis progression, including performance of cytokine arrays, micro-RNAs and measurement of IL28 polymorphisms. Emphasis is now also being placed on treatment.New treatments with direct acting antivirals can effect greater than 90% cure rates, but the new drugs are expensive and not readily available. Our goal is to treat as many patients as possible and effectively cure most of the patients in this cohort. Thus far,128 patients in this study have been treated to cure either with interferon based therapies or with new direct acting anti-virals. As we are treating the remaining HCV patients on protocol 18-DK-0091 we are also following them on two collaborative studies. The first study is to complete mRNA analysis pre and post treatment for studies of cell-mediated immune responses to HCV, neutralizing antibody responses, predictors of fibrosis progression, including performance of cytokine arrays, micro-RNAs and measurement of IL28 polymorphisms The second ongoing study is studying SICCA in HCV patients looking at changes in B Cells for both groups of patients and studying the B Cell changes in HCV patients after treatment and also documenting with patient completed surveys if treatment with a DAA helps their SICCA symptoms. In the current sexual partner arm of this study, we have enrolled 41 partners all of whom tested negative by both the initial screening test (EIA) and the specific HCV RNA PCR test. Twenty-one (51.2%) of those 41 partners had previously tested negative with an average duration between testing of 12.8 years. All partners were sexually active with index cases for at least 1 year and 71% never used any form of protective measure during sexual activity. Since approval of the hepatitis B arm of this study, we have enrolled 3 HBV positive patients. One patient had acute hepatitis B and was followed through her acute course to full recovery with treatment. The second patient was hepatitis B surface antigen (HBsAg) and HBV DNA positive at enrollment, but soon after became HBV DNA negative without treatment, but continues to be HBsAg positive. The third patient was strongly positive for HBsAg and for hepatitis B core antibody (anti-HBc). Further testing revealed that he was hepatitis B e antigen (HBeAg) negative and had very low level HBV DNA viral load and normal liver function (ALT) levels suggesting inactive infection.